Survival In Advanced Prostate Cancer Research Articles

Docetaxel/estramustine increases survival in advanced prostate cancer

Docetaxel/estramustine increases survival in advanced prostate cancer

Is prostate-specific antigen a surrogate for survival in advanced prostate cancer?

4551 Background: Surrogate endpoints are needed to shorten the duration of Phase III clinical trials in advanced prostate cancer. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer. This study attempts to validate PSA endpoints as surrogates for overall survival (OS). Methods: Individual data from 2161 patients with advanced prostate cancer treated in studies comparing bicalutamide (‘Casodex’), either as monotherapy or in combination with an LHRHa, with castration were used in a meta-analytical approach to surrogate endpoint validation. PSA response, several definitions of time to PSA progression and longitudinal PSA measurements were considered. Results: The analyses confirmed the known association between the PSA endpoints and OS at the individual patient level (biomarker association). However, when comparing patients treated with bicalutamide-based treatment or castration, the effect of hormonal intervention on the PSA endpoint did not predict the effect on OS with a high degree of precision. The association between intervention on any PSA endpoint and OS, measured by the determination coefficient R2 (ranging from 0.10–0.66 for PSA progression, to 0.69 for the whole PSA profile) was generally low. Conclusions: It is a common misconception that a correlation at the individual level between PSA and OS is enough to demonstrate surrogacy. To demonstrate true surrogacy, a high correlation between the treatment effect on the surrogate and the treatment effect on the true endpoint needs to be established across groups of patients treated with two alternative interventions. The level of association observed in this study between the treatment effect on PSA endpoints and that observed on OS was in general low, showing that in Phase III clinical trials of hormonal treatments in advanced prostate cancer, treatment effects on OS cannot be predicted from observed treatment effects on PSA endpoints with a high degree of precision. This study indicates that PSA is unlikely to be a useful surrogate for OS in advanced prostate cancer. ‘Casodex’ is a trademark of the AstraZeneca group of companies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca

Is prostate-specific antigen a surrogate for survival in advanced prostate cancer?

Is prostate-specific antigen a surrogate for survival in advanced prostate cancer?

Clusterin and IGFBPs as Antisense Targets in Prostate Cancer

The primary hurdle to improved survival of advanced prostate cancer is our failure to prevent or treat the tumor's progression to its lethal and untreatable stage of androgen independence. Novel treatment modalities designed to prevent androgen-independent progression including prostate cancer metastasis are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anticancer agents that specifically inhibit a progression-relevant target. Antisense oligonucleotides, short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene, promise to show enhanced specificity for malignant cells with a favorable side-effect profile due to well-defined and tailored modes of action. Although not all of the challenges have been met to date, emerging clinical evidence supports the premise that antisense oligonucleotides stand a realistic chance of emerging as major partners of rationally designed anticancer regimens. The rationale and status of antisense targeting of the treatment resistance factor clusterin and of insulin-like growth factor binding protein (IGFBP) 2 and 5 are discussed.

Antisense targets to enhance hormone and cytotoxic therapies in advanced prostate cancer.

The main obstacle to improved survival of advanced prostate cancer is our failure to prevent or treat its progression to its lethal and untreatable stage of androgen independence. New therapeutic agents designed to prevent androgen-independent progression are required. Accelerated identification and characterization of cancer-relevant molecular targets has sparked considerable interest in the development of new generations of anti-cancer agents that specifically inhibit a progression-relevant target. Antisense oligonucleotides, short synthetic stretches of chemically modified DNA capable of specifically hybridizing to the mRNA of a chosen cancer-relevant target gene. promise to show enhanced specificity for malignant cells with a more favorable side-effect profile due to well-defined and tailored modes of action. Although not all of the challenges have been met to date, emerging clinical evidence supports the premise that antisense oligonucleotides stand a realistic chance of emerging as major partners of rationally designed anti-cancer regimens. The status of antisense targeting of several genes, including bcl-2, bcl-xL, clusterin, androgen receptor and IGFBPs, relevant to prostate and other cancers, are reviewed.

Targeting anti-apoptotic genes upregulated by androgen withdrawal using antisense oligonucleotides to enhance androgen- and chemo-sensitivity in prostate cancer.

The main obstacle to improved survival of advanced prostate cancer is our failure to prevent its progression to its lethal and untreatable stage of androgen independence. New therapeutic strategies designed to prevent androgen-independent (AI) progression must be developed before significant impact on survival can be achieved. Characterization of changes in gene expression profiles after androgen ablation and during progression to androgen-independence suggest that the various therapies used to kill neoplastic cells may precipitate changes in gene expression that lead to the resistant phenotype. Castration-induced increases in antiapoptosis genes, Bcl-2 and clusterin, help create a resistant phenotype, while antisense oligonucleotides can inhibit these adaptive cell survival mechanisms and enhance both hormone and chemotherapy. Ongoing efforts are necessary to identify additional molecular pathways mediating AI progression and chemoresistance, since complexities of tumor heterogeneity and adaptability dictate that optimal control over tumor progression will require multi-target systemic therapies.

Strontium-89 improves survival in advanced prostate cancer

Strontium-89 improves survival in advanced prostate cancer